Is COG4 p.Asp778His (c.2332G>C) pathogenic?

COG4 p.Asp778His (c.2332G>C) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-28). Very rare (popmax 8.47e-05%, nfe); Associated with COG4-related disorder.

What condition is associated with COG4 p.Asp778His (c.2332G>C)?

COG4 p.Asp778His (c.2332G>C) is associated with COG4-related disorder (ClinVar).

How common is COG4 p.Asp778His (c.2332G>C) in the general population?

COG4 p.Asp778His (c.2332G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

COG4 p.Asp778His

c.2332G>C · rs1567718770 · VCV2631737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

COG4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.799	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.85e-05% 1/1,460,914 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COG4
Protein: p.Asp778His
Coding: c.2332G>C
MANE Select: NM_015386
dbSNP: rs1567718770
Type: single nucleotide variant
Location: chr16:70481048 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29 · 1 PDB
Residue 778: an α-helix; the 'e domain; essential for proper cell surface glycosylation' region

Full COG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG4-related disorder

Similar variants

COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Arg468Gln Uncertain significance ★★ same condition
COG4 p.Gln311Ter Likely pathogenic ★ same condition
COG4 c.844+5G>C Uncertain significance ★ same condition
COG4 p.Gly85Asp Uncertain significance ★ same condition
COG4 p.Thr680Pro Uncertain significance ★ same condition
COG4 p.Tyr50Phe Uncertain significance ★ same condition
COG4 c.1647+9C>G Uncertain significance same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cog4-p-asp778his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown